The type I receptor tyrosine kinase family is comprised of four closely related receptors: ErbB1 (EFGR or HER1), ErbB2 (HER2), ErbB3 (HER) and ErbB4 (HER4). These receptors are transmembrane glycoproteins which contain an extracellular domain for ligand binding and, with the exception of HER3, an intracellular catalytically active tyrosine kinase domain. These receptors transmit extracellular signals through the cytosol via a signal transduction cascade to the nucleus. The extracellular signal is transmitted by ligand binding to the dimeric receptor, with the exception of erbB2, of which a high affinity soluble ligand has yet to be identified. After ligand binding, the type I receptor tyrosine kinases either homodimerize or heterodimerize with another member of the subfamily of receptors (Lemmon M A, Experiment. Cell Res. (2009), 315:638-648). ErbB2 participates in this process by heterodimerization and is the preferred heterodimerization partner (Brennan P J, et al., Oncogene (2000), 19:6093). Dimerization leads to activation of the ErbB receptors by autophosphorylation of the intracellular domain. This autophosphorylation recruits adaptor proteins and leads to a phosphorylation cascade that transmits the signal throughout the cell. The type I receptor tyrosine kinase family (ErbB family) signals through the ras/raf/MEK/MAPK pathway as well as the PI3K/Akt pathway. These signaling pathways lead to both cell proliferation and cell survival through inhibition of apoptosis.
ErbB family receptors play important roles in cancer (Burgess A W, Growth Factors (2008), 26:263-74). Squamous carcinomas of the head and neck, and lung express high levels of EGFR. Also, constitutively active EGFR has been found in gliomas, breast cancer and lung cancer (Salomon, et al., Critical Rev. Oncol. Hematol. (1995), 19:183-232; Klapper, et al., Adv. Cancer Res. (2000), 77:25-79, and Hynes and Stern, Biochimica Biophysica Acta (1994), 1198:165-184). ErbB2 overexpression occurs in approximately 30% of all breast cancer (Milanezi, et al., Expert Rev. Mo. Diagnosis. (2008), 8(4), 417-34). ErbB2 is also implicated in other human cancers including colon, ovary, bladder, stomach, esophagus, lung, uterus and prostate. ErbB2 overexpression correlates with poor prognosis in human cancer, including metastasis, and early relapses (Baselga J and Swain S M, Nature Rev. Cancer (2009), 9:463-75).
The type I tyrosine kinase receptor family has been an active area of anti-cancer research (O'Donovan and Crown, Anticancer Res. (2007) 27(3A):1285-94). Several inhibitors of the EGFR and the ErbB2 signaling pathway have demonstrated clinical efficacy in cancer treatment. Herceptin, a humanized version of anti-ErbB2 monoclonal antibody, and panitumumab and cetuximab, two anti-EGFR monoclonal antibodies were approved for use in breast, colorectal, and head and neck cancers in the United States recently. Gefitinib (Iressa®) and erlotinib (Tarceva®) are small molecule inhibitors of EGFR that were launched for the treatment of certain solid cancers including lung cancer. In addition, lapatinib, a dual inhibitor of EGFR and ErbB2 was approved by FDA for treatment of metastatic breast cancer in 2007. A number of other antibodies and small molecules that target the interruption of the type I tyrosine kinase receptor signaling pathways are in clinical and preclinical development (Zhang, et al., J. Clin. Investigation (2007), 117:2051-2058), including some irreversible dual inhibitors of ErbB1, ErbB2 (Minkovsky N, Berezov A. Curr. Opin. Investig. Drugs. (2008); 9:1336-46; Bose P, Ozer H. Expert Opin. Investig. Drugs. (2009); 18:1735-51).
One significant unmet medical needs is the new treatment for primary brain tumor, particularly glioblastoma multiforme (GBM). A large percentage of GBM brain tumors harbors a disease-driving EGFR mutation, EGFRvIII. However, currently available EGFR small molecule inhibitors (erlotinib and gefitinib) and antibodies (cetuximab and panitumumab) have limited exposure in the brain due to their inefficiency to cross blood-brain-barrier (BBB) (Broniscer, et al., Clin. Cancer Res. (2007):1511; Lassman, et al., Clin. Cancer Res. 2005:7841). Therefore, they cannot be used for the treatment of GBM.
The incidence of metastasis to the brain is increasing in cancer patients, especially from the lung cancer, breast cancer and melanoma. The brain is considered a ‘sanctuary site’ as the blood-tumor barrier limits the ability of drugs to enter and kill tumor cells (Steeg, P S; et al., Nat. Rev. Cancer (2011) 11:352). Brain metastases from lung cancer account for 40-50% of all brain metastases, and close to half of these lung cancer brain metastases harbor EGFR mutations (Eichler, A F, et al., Neuro-Oncology (2010), 12:1193). Similarly, while use of Herceptin has significantly improved the outcome of HER2 positive breast cancer patients, many of these breast cancer patients developed brain metastases while being treated by Herceptin (http://www.cityofhope.org/eHope, 11(2) Feb. 21, 2012; Heitz, F.; et al., Ann. Oncol. (2011) 22:1571; Bendell, J. et al., Cancer (2003) 97:2972).
There is a continuing need for new cancer treatment and a significant unmet medical need for compounds capable of treating tumors in the brain.